Hepatocyte nuclear factor-1b controls mitochondrial respiration in renal tubular cells

Abstract

AKI is a frequent condition that involves renalmicrocirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor g coactivator 1-a (PPARGC1A), a coactivator of the transcription factor PPAR-g that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1b (HNF-1b) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1b transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-g and TNF-a led to inhibition of HNF-1b transcriptional activity. Moreover, inhibition of HNF-1b significantly reduced PPARGC1A expression and alteredmitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1b binding to the Ppargc1a promoter in mouse kidneys.We also demonstrated downregulation of renal PPARGC1A expression in a patient with an HNF1B germinal mutation. Thus, we propose that HNF-1b links extracellular inflammatory signals tomitochondrial dysfunction during AKI partly via PPARGC1A signaling. Our findings further strengthen the view of HNF1B-related nephropathy as a mitochondrial disorder in adulthood.